Cancer Cell International

C
CANCER CELL
INTERNATIONAL

BioMed Central

Open Access

Hypothesis

On evolutionary origin of cancer

Anatoly V Lichtenstein*
Address: Laboratory of Tumor Biochemistry, Cancer Research Center, Kashirskoye shosse 24, 115478 Moscow, Russia
Email: Anatoly V Lichtenstein* - alicht@online.ru
* Corresponding author

Published: 02 March 2005

Cancer Cell International 2005, 5:5

doi:10.1186/1475-2867-5-5

Received: 11 September 2004

Accepted: 02 March 2005

This article is available from: http://www.cancerci.com/content/5/1/5

2005 Lichtenstein; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Background: The necessary and sufficient capabilities of cancer cell have been identified.
Strikingly, this list does not include one that would seem to be a key property, namely the ability
of cancer cells to kill their "host". This is believed to be a self-evident consequence of the other
capabilities (e.g., metastasis), although the available evidence suggests a distinct killer function.
Taking into account this unlisted property can significantly affect the current paradigm of
carcinogenesis.
Presentation of the hypothesis: On the assumption that killer function is a key capability of the
cancer cell, it is suggested that cancer has evolved as a mechanism of negative selection of mutant
alleles of vitally important genes present in population. Similarly to apoptosis, which is an altruistic
suicidal act of a damaged cell, cancer is an altruistic suicidal act of an individual who carries
dangerous alleles and presents a hazard for genetic stability of the population. From this point of
view, apoptosis is not a protection means against cancer as generally believed, but rather they are
the first and second lines of defense against genome instability, respectively.
Testing the hypothesis: The modern DNA array technology is capable of revealing gene
expression profiles responsible for killer function of cancer cell as well as those specific targets in
the body that are most strongly affected by the tumor growth.
Implications of the hypothesis: This hypothesis suggests new avenues of cancer research as
well as principally new therapeutic strategies.

Background
We are now witnessing a post-genomic era of cancer
research. Thousands of papers are devoted to discovering
molecular mechanisms of this extremely complicated program, the latter term being understood as a prescribed
sequence of events with an inevitable result. In almost all
studies cancer is considered as a given entity with no
attempts made, to my knowledge, to search into its evolutionary origin. However, cancer almost certainly fulfills
some evolutionary tasks.

First, although cancer is usually mentioned as a representative of a large group of age-related diseases, it principally
differs from all the others. Cardiovascular diseases, diabetes, Alzheimer's disease, and many other diseases are
manifestations of the "loss-of-function" phenotype due to
degeneration and/or death of corresponding cells. Cancer,
on the contrary, is an active "gain-of-function" process.
Cancer cells acquire numerous new functions, including
the unique abilities to adapt to a changing environment
and to dodge the blows of the body's protective means, as
well as a striking capacity to recruit surrounding normal
Page 1 of 9
(page number not for citation purposes)

Cancer Cell International 2005, 5:5

tissues. The tumor transforms its natural enemies (normal

cells) into unnatural allies, being able to grow only having
such a paradoxical support [1-15]. The functional relations between normal and cancer cells are so diverse and
the tumor structure is so complex and hierarchical that a
growing tumor is sometimes viewed as a special developing "organ" [2,16]. Such an "organ" must have serious
evolutionary grounds to have evolved.
Second, cancer is an inevitable attribute of the animal
world. It hits every species despite the fact that there are
huge differences among them in the intracellular machinery, organization of signal pathways and, accordingly, in
anticancer defense (or, transformation resistance, see
below). In no case, however, is the anticancer defense of a
species high enough to exclude completely this illness,
despite presumably high cellular plasticity in this respect.
This fact would indicate some evolutionary advantages of
possessing such a trait. It seems likely that anticancer
defense of a species is counterbalanced by opposing forces
acting on the population level. In other words, cancer
incidence among a species is presumably maintained at
certain favorable level, which is coupled in each particular
case with an evolutionary adaptation of the intracellular
machinery.
In conclusion, evolutionary grounds for cancer seem to be
evident; it is the explanation of its expediency which
presents difficulties. A clue to this problem would be the
fact that cancer cell possesses, apart from the well known
necessary and sufficient capabilities [17], a killer function
directed against the host. Strikingly, this evident capability
that seems to be a key property of the tumor cell does not
attract the attention it deserves. It is believed to be a selfevident consequence of the other traits that constitute the
malignant phenotype, although the available evidence
would rather suggest that killer function is a distinct capability. Taking into account this overlooked property, one
can view cancer as a suicidal act of an individual, since the
inevitable outcome of this illness is demise (if treatment
is absent or delayed). By analogy with apoptosis, which
has evolved as altruistic suicidal act of a damaged cell [18]
that otherwise would threaten the genetic stability of the
cell population, cancer might be viewed as an individual
suicidal act that brings some benefits to the population.

Presentation of the hypothesis

Killer function is a key capability of the cancer cell
Carcinogenesis is a multistage process of accumulation of
gene defects that determine the characteristic traits of the
cancer cell: self-sufficiency in growth signals, insensitivity
to anti-growth and pro-apoptosis signals, limitless replicative potential, sustained angiogenesis, tissue invasion,
and metastasis [17]. These acquired capabilities determine the malignant phenotype of a cell but do not explain

http://www.cancerci.com/content/5/1/5

the clinical manifestations of cancer. Indeed, it seems

astonishing that the human body, which consists of ca.
1014 cells, can not endure a relatively small fraction of cancer cells (0.01 0.1% of the total), this burden often being
incompatible with life. Rarely, the immediate cause of
death is evident (brain compression, bleeding, perforation of the intestine), but in general it remains obscure.
This suggests a deadly influence of cancer upon the body
through some unknown mechanisms. Although each of
many different forms of cancer has clinical peculiarities,
the overall course of the illness and the final result are
always the same. So, the notion that the tumor cell,
regardless of origin, possesses a special killer function is a
statement of an obvious fact. What is surprising in this
regard is that no room has been allocated to it in the existing paradigm of carcinogenesis.
Paraneoplastic syndromes present evidence that tumors
may affect normal tissues remote from the primary site.
These syndromes are extremely diverse and affect almost
all organs and tissues [19]. The most frequent clinical
manifestations are cachexia, anorexia, nausea, neuropathy, retinopathy, general sickness, and malfunctions of
many body systems. A long time (16 to 20 months) before
cancer is diagnosed, some patients show body weight loss,
which is indicative that even at early stages tumors may
have a generalized effect upon the body, which increases
progressively with tumor growth [20]. Since, however,
pronounced cachexia (a loss of more than 5% body
weight) occurs in about a third of patients and becomes
the cause of death in only 20% of the cases [21], it is clear
that tumor cells have other, yet unrecognized means of
killing the body.
It remains unknown whether the paraneoplastic syndromes are direct manifestations of the killer function
itself or they are mere side effects of tumor growth, such
as autoimmune diseases. It is noteworthy that cancer is
not always accompanied by paraneoplastic syndromes
[22], yet its killer function never fails. On the other hand,
the most effective treatment of paraneoplastic syndromes
is specific cancer therapy, while the reverse approach, a
symptomatic treatment targeted at particular manifestations of tumor growth, rarely gives positive results and
never offers a radical cure. This fact suggests that most of
the mentioned effects, justifying their name of paraneoplastic, take place not within the killer function pathway
but somewhere aside. Because of this, the term killer function will be used here, without going into its mechanism,
as indicating the obvious capability of cancer cells to kill
the body.
The killer capability is crucial to the achievement of the
final goal, body demise, whereas all the other, promoting
proliferation and spread of killer cells are de facto only

Page 2 of 9
(page number not for citation purposes)

Cancer Cell International 2005, 5:5

(a)
T
R
I

(b)

G
G
E
R

(c)
.
.
.
.
(n)

http://www.cancerci.com/content/5/1/5

m(0)
m(1)
m(2)
m(3)

.
.
.

m(n)

Figure 1 accumulation of specific gene defects

Step-wise
Step-wise accumulation of specific gene defects.
Mutations (red triangles) trigger the built-in cell killer function (red asterisks). m(0), normal cells; m(1), m(2), m(3),
m(n), mutant cells with 1, 2, 3, and n defects in cancerrelated genes, respectively. (a), (b), (c), (n), selection "sieves"
which determine the stages of transformation. The trigger
"count-down" is shown on the left. Double-headed arrows
indicate that transformation and trigger steps are amenable
to species- and tissue-specific variations (see text).

accessory. It seems to be a distinct capability of cancer

cells, rather than a derivative of other capabilities, such as
uncontrolled proliferation and metastasizing. It is
unlikely that active proliferation can by itself exert such a
deleterious effect since dozens of billions of cells divide
daily in the human body, which is many-fold greater than
the proliferation pool of the biggest tumor. Even the
metastases, these relatively small foci of ectopic proliferation, can not account by themselves for the inevitable
demise. The killer function is also a universal property of
the cancer cell since without treatment the lethal outcome
is inevitable no matter what is the type of tumor, its ability
to develop metastases, recur, induce cachexia, or affect
biochemical indices. Finally, this property is specific to
the cancer cell, as in normal cell physiology there are no
examples of such activity.

The killer function seems radically different from all other

acquired capabilities in that it apparently gives no selective advantage to the cancer cell. On the contrary, for the
latter, as a part of the body, acquiring such a function is
the same as committing suicide. This changes radically the
understanding of the role of cancer cells: they can be
regarded not as selfish "cheats" [23], which propagate at
the expense of all others, but rather as altruists which sacrifice themselves and the whole body for the sake of some
higher (apparently population) benefits, as suggested in
the recent hypothesis of phenoptosis [24].
Mutations as death program trigger
As cancer cells do not acquire selective advantages during
realization of their killer function, it seems unlikely that
the latter is created each time de novo in the same way as
the other properties are, namely in the way of numerous
step-by-step cycles of mutation-selection. Rather, the cells
possess a built-in and ready-for-use program of deadly
events, which, just like apoptosis, is launched under certain conditions and then functions automatically. In such
a case, mutations of cancer-related genes are not only
transformation steps, as generally considered, but also a
trigger countdown mechanism that activates the death
program directed against the "host". This dual activity
leads to appearance of an expanding clone of killer cells
progressively strengthening their effect upon the organism
(Fig. 1).

A specific feature of the genetic defects underlying the

tumor phenotype is that they do not decrease cell viability
(basic cellular functions, in contrast to specialized, are
even enhanced). In a certain sense, these are the defects of
not the cell per se but rather of the cell/organism "interface" that mediates subordination of cell functions to the
common interests. Under normal conditions, numerous
signal pathways tie the cell to the tissue homeostasis
mechanism, whereas their defects are nothing but a stepwise liberation of the cell from its "fetters". The number of
liberating mutations necessary for cell transformation to
occur ranges from 4 to 12 [25,26], this value being a quantitative measure of the cell "transformation resistance". If
one can compare the cancer cell with an explosion device
aimed at destroying the body, then mutagenesis serves
there the function of a trigger countdown clock with 412
intermediate positions (Fig. 1).
Peto paradox
Cell transformation is an extremely rare event because it
requires the coincidence in a single cell of several very
improbable events [26-28]. However, the life-span risk of
human cancer is high (ca. 20%) because of a huge number
of cells in the body (ca. 1014) and large longevity. Indeed,
no matter how unlikely is the event by itself it has a real
chance to occur under such conditions. If so, one might

Page 3 of 9
(page number not for citation purposes)

Cancer Cell International 2005, 5:5

suggest that animals with a small body weight and short

life-span (e.g., rodents) should not suffer from cancer at
all, while big animals (whales) should get cancer in their
mothers' wombs. Reality, however, does not follow this
theory's predictions (the well known Peto paradox [29]).
All animals regardless of body weight and longevity suffer
from cancer, but, on the other hand, cancer incidence
does not threaten the species existence.
The Peto paradox is explained by various transformation
resistance of cells from different species [23,30]. This may
be due to (i) different efficiency of DNA repair systems,
(ii) difference among species in the degree of selective
advantages acquired by the cell from similar mutations
[30], (iii) different setting up of the trigger (e.g., more signal pathways have to be damaged to transform human
than mouse fibroblasts [31]). The trigger is probably most
reliable (i.e., has a greatest number of intermediate positions) in whale cells and least reliable in mouse cells.
The Peto paradox can apparently be applied to body tissues as well [23]. Indeed, cancer develops in all human tissues, which differ greatly in the number of cells as well as
their proliferation activity. Just as in the case of interspecies variability, it can be assumed that cells of different tissues have different transformation resistance [32,33]. The
presented examples suggest that the transformation resistance of cells from different tissues and species underwent
evolutionary adaptation to the selective pressure exerted
by tumor growth [23].
Cancer is a local manifestation of generalized mutagenesis
Most patients develop only one tumor, which presents
carcinogenesis as allegedly a local process. Experiments
with exposure of animal skin to chemical carcinogens as
well as cases of occupational cancer, which demonstrate
clearly the link between site of exposure and tumor localization, support this notion. Without questioning the significance of such observations, they seem to have an
exceptional and limited character (see below).

In fact, mutagenesis is intimately related to metabolism

and is therefore omnipresent: every day in each cell many
thousands of DNA lesions occur due to replication and
repair errors, spontaneous depurination, methylcytosine
deamination, reactive oxygen species attacks, and telomere shortening. This list should perhaps be extended to
include the mutagenic effect of apoptosis resulting from
uptake by phagocytosis of DNA from dead cells [34].
Because of imperfect repair of DNA damage, the mutation
rate is estimated to vary in the range of 10-410-8 per gene
per cell division [26,27]; mutations occur in all tissues
and increase with age [10,27,35,36]. Calculations show,
for instance, that by the age of 65 over 105 mutations accu-

http://www.cancerci.com/content/5/1/5

mulate in the normal stem cell of human colonic crypt

[28].
When a tumor nodule appears in the body, it seems to be
only the tip of an iceberg, maturing in the body for decades and consisting of a multitude of damaged cells at different stages of transformation. This assumption is
supported by the clinical experience showing that overt
symptoms of the disease are always preceded by precancerous lesions, such as hyperplasia, metaplasia, and dysplasia. This idea finds further development in the concept
of "field cancerization", i.e., large (more than 7 cm in
diameter) and surrounding the tumor "patches" of damaged cells, recognized on the basis of mutations in TP53,
but remaining undetectable by routine diagnostic techniques [37].
Similar conclusions can be drawn from a notion of mutation as a random and rare event and carcinogenesis as
accumulation of genetic defects. Mutagenesis can be
described as the process both extensive (measured by
number of affected cells) and intensive (measured by
number of mutations per individual cell). Evidently, these
parameters are positively correlated with each other: the
wider the damaged zone, the deeper the damage of individual cells. The reverse is also true: the deeper the damage
of the individual, most "advanced" cells, the wider the
lesion area (this means that the very fact of a tumor
appearance is, in general, the sign of a significant mutagenic lesion). In other words, appearance of the cell having a complete set of mutations (i.e., cancer cell) is
accompanied by formation of a large pool of precancerous cells.
The simple model of accumulation of mutant cells (i.e.,
cells with 14 mutations, the latter being the arbitrary
transformation threshold) in an exponentially growing
cell population is shown in Fig. 2. With time mutant cells
inevitably appear [28], since mutagenic load is increasing
and the repair systems become less efficient [35]. The first
to appear and start to grow is a layer of cells with one
defect, then a layer of cells with two defects, and so on.
Each subsequent cell layer grows quicker than the preceding one because each new mutation confers a selective
advantage to affected cells [38]. Additional momentum is
conferred to the entire process by acquisition of chromosomal instability [39] or a mutator phenotype [26]. At
each stage of carcinogenesis, transition from quantity (of
damaged cells) to quality (a cell with a new mutation)
takes place, the latter having a chance to appear only from
a large enough pool of its predecessors. On the whole,
maturation of a tumor looks like a "pyramid" growing
until a completely transformed cell appears at its top. The
latter gives rise to the overt tumor. The overall process may
be symbolized by a "mushroom", in which the "stem"

Page 4 of 9
(page number not for citation purposes)

Cancer Cell International 2005, 5:5

k=12

a
m(1)
m(0)

1
4 x 103

k=23

b
m(2)
m(1)
m(0)

1
3.9 x 103
8.4 x 106

k=34

c
m(3)
m(2)
m(1)
m(0)

http://www.cancerci.com/content/5/1/5

m(4)
m(3)
m(2)
m(1)
m(0)

1
3.9 x 103
1.2 x 107
1.7 x 1010

k=45

1
3.9 x 103
1.4 x 107
3.1 x 1010
3.5 x 1013

k>45

Overt tumor
m(4)
m(3)
m(2)
m(1)
m(0)

Latent growth

Figure 2 of cancer "mushroom" in exponentially growing tissue

Maturation
Maturation of cancer "mushroom" in exponentially growing tissue. k, cycles of cell exponential growth; u, 4 10-5. a
e, stages of carcinogenesis. m(0), normal cells; m(1), m(2), m(3), and m(4), mutant cells with 1, 2, 3, and 4 mutations in cancer-related genes, respectively. Cell numbers in each layer are indicated on the right (see text).

Page 5 of 9
(page number not for citation purposes)

Cancer Cell International 2005, 5:5

and "cap" are the latent and overt stages, respectively (Fig.
2).
It follows from the model of multistage carcinogenesis
[23] that in an exponentially growing tissue the number
of mutant cells is approximated by the formula

k
am

1 ku k

2 e
m! 2

ku
2 ,

k
where am
is the mean number of cells with m mutations
after k cell generations and u is the mutation rate. If we
assume that the body is composed of 3.5 1013 cells (i.e.,
245, k = 45), and u is 4 10-5 (for a single gene u is 4 107, thus if there are one hundred cancer-related genes u
becomes 4 10-5 [40]), then at the moment of appearance
in the body of the cell with 4 mutations (a tumor
founder), there will be ~3.9 103 cells with 3 mutations,
~1.4 107 cells with 2 mutations, and ~3.1 1010 cells
with 1 mutation (Fig. 2d). In other words, in the human
body one cell from every thousand (0.1%) will be
mutated at least in one of the cancer-related genes. In reality, mutation frequency should be much higher because
cell death occurs during developmental growth so that
replenishing cell divisions must increase k value significantly. This calculation, though very approximate, agrees
with experimental data [27] and can give an idea of the
magnitude of the mutation frequency (see also [28]).
They might indicate that cancer appears as mutation frequency reaches a certain security threshold. On the other
hand, this calculation showing that the human body is
flooded with mutant cells prior to tumor appearance
points to the validity of chemoprevention as an essential
approach to controlling cancer [41].

http://www.cancerci.com/content/5/1/5

fests significant whole body mutagenesis, then germ cells

are most probably not an exception: a similarity of spontaneous germinal and somatic cell mutation rates was
shown for human cells in vitro [42]. High levels of somatic
mutation seem to be a direct reflection of the germ line
mutation rate selected over evolutionary time [35]. Due to
its prolonged solitary existence and relative lack of protective, repair and self-destruction mechanisms, sperm cells
may be even more susceptible to genetic damage than
somatic cells [27,43,44]. Besides, some gene mutations
are paradoxically enriched because they confer a selective
advantage to the spermatogonial cells in which they arise
[45,46]. In conclusion, germ cells are apparently not protected from mutagenesis more reliably than somatic cells
are. If so, one can hypothesize that the killer program (i.e.,
cancer) is unleashed in a somatic cell when its vital ("cancer-related") genes are damaged to such an extent that testifies to intolerably high mutation frequency in body
tissues and, most importantly, in germ cells ("in mutant
soma a mutant semen" principle). This may endanger the
genetic stability of the population. Therefore, if at the cellular level cancer cells look like aggressive "cheats" [23], at
the body level the process may be an altruistic suicide to
remove mutant alleles from the genetic pool.

Cancer as a mechanism of negative selection of mutant

alleles
As discussed above, the size of the fraction of pre-malignant cells is dependent on trigger tuning the more mutations needed for a malignant transformation, the bigger
the pool of damaged cells. Hence, the first completely
transformed cell plays de facto a triple role: (i) a sensor for
general mutagenesis (since its "trigger clock" counts down
in accordance with accumulation of mutant cells in the
body), (ii) an executioner that unleashes a built-in death
program after mutagenesis exceeds some threshold level,
and (iii) a founder of a clone of killer cells. Any stem cell
in an organism can apparently play such a triple role, thus
ensuring reliability of the mechanism.

While in the case of sporadic tumors the notion that cancer is a local manifestation of generalized mutagenesis is
only a more or less validated assumption, it is a truism in
the case of hereditary tumors [47]. Carcinogenesis in such
an individual has significant "odds" compared to wildtype individuals [11] because all his cells are mutant (the
trigger, in other words, has been moved one position
ahead from the very outset). The association between the
evident threat of germinal mutations to the population,
on one hand, and their extremely high cancer risk, on the
other, seems not to be by chance. The life-span risk of getting cancer for persons with germinal mutations in the
suppressor genes reaches 5080%, and their tumors,
often multiple, appear at a reproductive age [11]. Owing
to an extremely strong selection pressure, the alleles that
predispose to cancer are very rare (ca. 1:1000 or less), suggesting that the mechanism is efficient. The most convincing argument for the hypothesis that malignant tumors
have an altruistic function comes from hereditary forms of
cancer in which the association "mutant semen in a
mutant soma" is most evident. The altruism here is that
the carriers of mutant alleles die at a reproductive age. It is
germinal mutations arising in a population with a certain
frequency that could have been the driving force for cancer evolution.

Evolutionary conservation of the death program prompts

us to look for an explanation for its appearance. It may
consist of the counter-selection of genetically defective
individuals. As a matter of fact, if an arising tumor mani-

It is evident that the greater the number of pre-cancerous

stages, the more strongly the individual is protected
against cancer. A computational model of cancer progression was elaborated recently to show that the appearance

Page 6 of 9
(page number not for citation purposes)

Cancer Cell International 2005, 5:5

of an extra stage and the additional buffering, which arises

as a result, reduce the impact of any single hereditary
mutation and therefore allow the accumulation of more
nonlethal mutations in the population [48]. Because natural selection cannot purge mutations that are mostly hidden by robust pathways, mutations will continue to
accumulate until their consequences become sufficiently
deleterious that they are balanced by natural selection. An
additional protection from cancer by extra stages thereby
leads to the evolution of partially decreased cancer mortality and significantly increased genetic variability in the
population as a whole [49]. This point of view is in
accordance with the assumption that if such purging
mechanism as cancer was absent, deleterious mutations
would be widespread in the population.
There are many germinal mutations with phenotypic
expression but just a few of them (affecting a small group
of ~50 genes [50,51]) are linked with hereditary cancer.
Probably, only mutations in key genes that present the
greatest threat to the population are prevented by this
mechanism from being spread. Many other germinal
mutations are unable to pass the "sieve" of embryonic
development because they induce early abortions [27].
There are a number of barriers to prevent spreading of
mutant alleles in a population, and cancer seems to be
only one of them.
A favorable trait is retained only if it manifests itself during the reproductive period. So, the fact that cancer is predominantly a disease of the elderly would seem to be at
conflict with a supposition of its evolutionary significance. This is perhaps an apparent conflict: the incidence
of cancer among the young may be relatively low exactly
because of the efficient selection against the adverse alleles that constantly appear in the population and exist as
an inevitable background. As regards the high incidence
of cancer at the old age, which seems to have no evolutionary significance, this can be explained from the viewpoint of the evolutionary theory of antagonistic
pleiotropy [52]. A genetic program that has played a positive role in youth continues to be active in the older age,
despite its possible counter-productive effects, simply
"from force of inertia" because no correction mechanisms
are available [53]. This, together with an increased mutation and weaker repair, results in the exponential growth
of cancer incidence in old age [10,35].
Germinal mutations in functionally important genes are a
strong stimulus for development of a mechanism to prevent their spread in the population. Apart from these
highly penetrant rare alleles with a strong hereditary predisposition to cancer, which are merely eradicated from
the population, there are many alleles that determine a
weak predisposition [49] (their cumulative effect can be

http://www.cancerci.com/content/5/1/5

very significant [11,54,55]). The frequency of such alleles

in a population seems to be negatively correlated with the
cancer risk they contribute.
There is another apparent contradiction between the thesis that tumor appearance manifests generalized mutagenesis and the numerous cases when a tumor is clearly
linked with a local exposure inflammation, bacterial
infection, or UV-irradiation. The occupational cancer, on
one hand, and experimentally induced tumors in animals,
on the other hand, makes this association unquestionable. This linkage is probably a side effect of the evolutionary mechanism described here, in which the tumor cell
plays a dual role, the mutagenesis sensor and the death
program executor. In such a mechanism, a local fluctuation can unleash a process even when the overall mutation level is low (similarly, a sensor designed to respond
to whole system temperature is activated by a local
heating).
In carcinogenesis, the hypothetical sensor/executor functions under the conditions of continuous interference and
noise, which are generated by numerous external and
internal locally acting mutagens. From this, many false
actions ensue. If one takes the hypothesis that cancer is a
means of protection, one must admit that in humans this
mechanism is hyperactive and operates beyond the originally set objectives. Both the high cancer incidence in old
age and the multitude of cancer cases resulting from local
exposure to carcinogens are examples of this hyperactivity
that obscure the true evolutionary nature of the
phenomenon.
Evolution hypotheses that attempt at explaining the
appearance of cooperation and altruistic behavior are
based on the ideas of kin or group selection [56,57]. Their
weakness is sometimes seen as an inequality between
gross individual losses and relatively small population
benefits, thereby questioning the validity of the proposed
mechanisms. However, in the case of germinal mutations
affecting important genes, the threat of genetic imbalance
in the population is perhaps so high (see [48]) that it justifies the individual losses due to such a protection means
as cancer. Here again one can perceive an analogy with
cell suicide, which is likewise hyperactive in "forestalling"
the potentially hazardous consequences of genetic defects
(a weakening of such a preventive defense is undesirable
[58]).
Maintaining DNA integrity is one of the main priorities of
living organisms. Depending on the extent of DNA damage, three outcomes are possible: (i) small damage
induces repair which restores the initial state; (ii) strong
damage launches apoptosis thus preventing cell-to-cell
transfer of damaged DNA; (iii) accumulating lesions,

Page 7 of 9
(page number not for citation purposes)

Cancer Cell International 2005, 5:5

http://www.cancerci.com/content/5/1/5

when apoptosis is impossible, trigger cancer thus preventing individual-to-individual transfer of damaged alleles of
vitally important genes. From this point of view, apoptosis is not a protection means against cancer as generally
believed, but rather they are the first and second lines of
defense against genome instability, respectively.

Acknowledgements

Testing the hypothesis

2.

A striking discovery was made recently that a tumor can

survive, propagate, and spread in the body only through
the unnatural help coming from normal tissues [6,13,59].
One more step further in elucidation of tumor-host relationships is yet to be made, namely, a discovery of a mechanism of killer function. Although it is this feature that
imparts so much significance to malignant growth, the
current paradigm of carcinogenesis does not envisage the
killer function as some special property; as a result, this
function does not attract the attention it deserves. Meanwhile, there are possibilities to unveil the mechanism of
tumor malignancy at present. The modern DNA array
technology is capable of revealing gene expression profiles
responsible for killer function. This can be done by comparison of (i) malignant tumors having different expression of this trait and (ii) benign and malignant tumors.
Besides, identification of genes responsible for killer function is to be supplemented, using the same technology,
with serial analyses of expression profiles of various
organs and tissues of tumor-bearing animals at various
stages of tumor progression. This can help to identify
those specific targets within the body that are most
strongly affected by the tumor growth.

I thank G. Sardanashvilli for help in mathematics and V. Gurtsevitch and B.

Kopnin for helpful discussions. This work was supported in part by the Russian Foundation for Basic Research (grant 04-04-48094).

References
1.

3.
4.

5.
6.
7.
8.
9.

10.
11.
12.
13.
14.
15.
16.
17.

Implications of the hypothesis

18.

Recognition of killer function as a crucial capability of

cancer cells suggests not only new avenues of cancer
research (see above), but also principally new therapeutic
strategy. Achievement of better understanding of mechanisms of body death may help to pinpoint new targets for
therapy, such as some factors presumably emitted by cancer cells (unusual cytokines, for example), that exert the
deadly effect. These factors are likely to be cancer-specific,
so their elimination would not entail severe side effects.
The present day cancer therapy is based, without much
success, on the imperative to "exterminate the evil" (i.e.,
the cancer cells). The essence of an alternative strategy
which may turn out to be more effective is not to kill the
cancer cells, but to neutralize them.

21.

Competing interests

26.

The author(s) declare that they have no competing

interests.

27.

19.
20.

22.
23.
24.
25.

28.
29.

Bergers G, Benjamin LE: Tumorigenesis and the angiogenic

switch. Nat Rev Cancer 2003, 3:401-410.
Bissell MJ, Radisky D: Putting tumours in context. Nature Rev
Cancer 2001, 1:46-54.
Elenbaas B, Weinberg RA: Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation.
Exp Cell Res 2001, 264:169-184.
Elenbaas B, Spirio L, Koerner F, Fleming MD, Zimonjic DB, Donaher
JL, Popescu NC, Hahn WC, Weinberg RA: Human breast cancer
cells generated by oncogenic transformation of primary
mammary epithelial cells. Genes Dev 2001, 15:50-65.
Friedl P, Wolf K: Tumour-cell invasion and migration: diversity
and escape mechanisms. Nat Rev Cancer 2003, 3:362-374.
Jacks T, Weinberg RA: Taking the study of cancer cell survival
to a new dimension. Cell 2002, 111:923-925.
Liu X, Sun Y, Weinberg RA, Lodish HF: Ski/Sno and TGF-beta
signaling. Cytokine Growth Factor Rev 2001, 12:1-8.
Schmitt CA: Senescence, apoptosis and therapy - cutting the
lifelines of cancer. Nat Rev Cancer 2003, 3:286-295.
Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier
N, Boon T, Van Den Eynde BJ: Evidence for a tumoral immune
resistance mechanism based on tryptophan degradation by
indoleamine 2,3-dioxygenase. Nat Med 2003, 9:1269-1274.
DePinho RA: The age of cancer. Nature 2000, 408:248-254.
Ponder BA: Cancer genetics. Nature 2001, 411:336-341.
Liotta LA, Kohn EC: The microenvironment of the tumourhost interface. Nature 2001, 411:375-379.
Hendrix MJ, Seftor EA, Hess AR, Seftor RE: Vasculogenic mimicry
and tumour-cell plasticity: lessons from melanoma. Nat Rev
Cancer 2003, 3:411-421.
Dranoff G: Cytokines in cancer pathogenesis and cancer
therapy. Nat Rev Cancer 2004, 4:11-22.
Pollard JW: Opinion: Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004,
4:71-78.
Perez-Losada J, Balmain A: Stem-cell hierarchy in skin cancer.
Nat Rev Cancer 2003, 3:434-443.
Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000,
100:57-70.
Ameisen JC: On the origin, evolution, and nature of programmed cell death: a timeline of four billion years. Cell Death
Differ 2002, 9:367-393.
Finora K: Common paraneoplastic syndromes. Clin Tech Small
Anim Pract 2003, 18:123-126.
Kritchevsky SB, Wilcosky TC, Morris DL, Truong KN, Tyroler HA:
Changes in plasma lipid and lipoprotein cholesterol and
weight prior to the diagnosis of cancer. Cancer Res 1991,
51:3198-3203.
Tisdale MJ: Cachexia in cancer patients. Nat Rev Cancer 2002,
2:862-871.
Ou YC, Yang CR, Ho HC, Cheng CL, Kao YL, Su CK, Chiu KY, Chen
WM: The symptoms of renal cell carcinoma related to
patients' survival. J Chin Med Assoc 2003, 66:537-543.
Nunney L: Lineage selection and the evolution of multistage
carcinogenesis. Proc R Soc Lond B Biol Sci 1999, 266:493-498.
Skulachev VP: Programmed death phenomena: from organelle
to organism. Ann N Y Acad Sci 2002, 959:214-237.
Den Otter W, Koten JW: A 4-mutation model of carcinogenesis for tumour suppressor genes. Anticancer Res 1999,
19:4845-4852.
Loeb LA: A Mutator Phenotype in Cancer. Cancer Res 2001,
61:3230-3239.
Vijg J: Somatic mutations and aging: a re-evaluation. Mutat Res
2000, 447:117-135.
Tomlinson I, Sasieni P, Bodmer W: How many mutations in a
cancer? Am J Pathol 2002, 160:755-758.
Peto R, Roe FJ, Lee PN, Levy L, Clack J: Cancer and ageing in mice
and men. Br J Cancer 1975, 32:411-426.

Page 8 of 9
(page number not for citation purposes)

Cancer Cell International 2005, 5:5

30.
31.
32.
33.
34.
35.
36.
37.

38.
39.
40.
41.
42.

43.
44.
45.
46.

47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.

Leroi AM, Koufopanou V, Burt A: Opinion: Cancer selection. Nat

Rev Cancer 2003, 3:226-231.
Hahn WC, Weinberg RA: Modelling the molecular circuitry of
cancer. Nat Rev Cancer 2002, 2:331-341.
Renan MJ: How many mutations are required for tumorigenesis? Implications from human cancer data. Mol Carcinog 1993,
7:139-146.
Knudson AGJ: Mutation and cancer: statistical study of
retinoblastoma. Proc Natl Acad Sci U S A 1971, 68:820-823.
Holmgren L, Szeles A, Rajnavolgyi E, Folkman J, Klein G, Ernberg I,
Falk KI: Horizontal transfer of DNA by the uptake of apoptotic bodies. Blood 1999, 93:3956-3963.
Simpson AJ: The natural somatic mutation frequency and
human carcinogenesis. Adv Cancer Res 1997, 71:209-240.
Campisi J: Aging and cancer: the double-edged sword of replicative senescence. J Am Geriatr Soc 1997, 45:482-488.
Braakhuis BJM, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH:
A Genetic Explanation of Slaughter's Concept of Field Cancerization: Evidence and Clinical Implications. Cancer Res
2003, 63:1727.
Tomlinson IP, Novelli MR, Bodmer WF: The mutation rate and
cancer. Proc Natl Acad Sci U S A 1996, 93:14800-14803.
Nowak MA, Komarova NL, Sengupta A, Jallepalli PV, Shih IM, Vogelstein B, Lengauer C: The role of chromosomal instability in
tumor initiation. Proc Natl Acad Sci U S A 2002, 99:16226-16231.
Frank SA, Nowak MA: Cell biology: Developmental predisposition to cancer. Nature 2003, 422:494.
Sporn MB, Suh N: Chemoprevention: an essential approach to
controlling cancer. Nat Rev Cancer 2002, 2:537-543.
Kuick RD, Neel JV, Strahler JR, Chu EH, Bargal R, Fox DA, Hanash
SM: Similarity of spontaneous germinal and in vitro somatic
cell mutation rates in humans: implications for carcinogenesis and for the role of exogenous factors in "spontaneous"
germinal mutagenesis. Proc Natl Acad Sci U S A 1992,
89:7036-7040.
Aitken RJ, Koopman P, Lewis SEM: Seeds of concern. Nature 2004,
432:48-52.
Masters JR, Koberle B: Curing metastatic cancer: lessons from
testicular germ-cell tumours. Nat Rev Cancer 2003, 3:517-525.
Goriely A, McVean GA, Rojmyr M, Ingemarsson B, Wilkie AO: Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science 2003, 301:643-646.
Tiemann-Boege I, Navidi W, Grewal R, Cohn D, Eskenazi B, Wyrobek
AJ, Arnheim N: The observed human sperm mutation frequency cannot explain the achondroplasia paternal age
effect. Proc Natl Acad Sci U S A 2002, 99:14952-14957.
Knudson AG: Hereditary predisposition to cancer. Ann N Y Acad
Sci 1997, 833:58-67.
Frank SA: Genetic variation in cancer predisposition: mutational decay of a robust genetic control network. Proc Natl
Acad Sci U S A 2004, 101:8061-8065.
Frank SA: Genetic predisposition to cancer - insights from
population genetics. Nat Rev Genet 2004, 5:764-772.
Knudson AG: Antioncogenes and human cancer. Proc Natl Acad
Sci U S A 1993, 90:10914-10921.
Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R,
Rahman N, Stratton MR: A census of human cancer genes. Nat
Rev Cancer 2004, 4:177-183.
Kirkwood TB, Austad SN: Why do we age? Nature 2000,
408:233-238.
Campisi J: Cancer and ageing: rival demons? Nat Rev Cancer
2003, 3:339-349.
Demant P: Cancer susceptibility in the mouse: genetics, biology and implications for human cancer. Nat Rev Genet 2003,
4:721-734.
Peto J, Houlston RS: Genetics and the common cancers. Eur J
Cancer 2001, 37 Suppl 8:S88-S96.
Hamilton WD: The genetical evolution of social behaviour. I
and II. J Theor Biol 1964, 7:1-52.
Maynard-Smith J: Group selection and kin selection. Nature 1964,
201:1145-1147.
Camplejohn RS, Gilchrist R, Easton D, McKenzie-Edwards E, Barnes
DM, Eccles DM, Ardern-Jones A, Hodgson SV, Duddy PM, Eeles RA:
Apoptosis, ageing and cancer susceptibility. Br J Cancer 2003,
88:487-490.

http://www.cancerci.com/content/5/1/5

59.

Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S,

Washington MK, Neilson EG, Moses HL: TGF-{beta} Signaling in
Fibroblasts Modulates the Oncogenic Potential of Adjacent
Epithelia. Science 2004, 303:848-851.

Publish with Bio Med Central and every

scientist can read your work free of charge
"BioMed Central will be the most significant development for
disseminating the results of biomedical researc h in our lifetime."
Sir Paul Nurse, Cancer Research UK

Your research papers will be:

available free of charge to the entire biomedical community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central
yours you keep the copyright

BioMedcentral

Submit your manuscript here:

http://www.biomedcentral.com/info/publishing_adv.asp

Page 9 of 9
(page number not for citation purposes)